S266: OXYGEN GRADIENT EKTACYTOMETRY-DERIVED BIOMARKERS ARE ASSOCIATED WITH THE OCCURRENCE OF ACUTE COMPLICATIONS IN SICKLE CELL DISEASE
Authors: M. Rab, C. Kanne, C. Boisson, J. Bos, B. van Oirschot, M. Houwing, C. Renoux, R. Schutgens, M. Bartels, A. Rijneveld, E Nur, M. Cnossen, P. Joly, R. Fort, P. Connes, R. van Wijk, V. Sheehan, E. van Beers
Journal: HemaSphere (2022)

Background: Sickle cell disease (SCD) is a monogenetic disorder with a highly complex pathophysiology. There is an unmet need for robust reproducible biomarkers that can assess red blood cell (RBC) function and predict disease severity and complications. Aims: To explore the association between oxygen gradient ektacytometry-derived biomarkers, and blood viscosity with incidence of major (acute) SCD-related complications. Methods: Oxygen gradient ektacytometry measures RBC deformability continuously while the sample is gradually deoxygenated and subsequently reoxygenated, and identifies the oxygen tension at which sickling occurs. We examined associations between the occurrence of acute chest syndrome, cerebral infarction and vaso-occlusive crisis (VOC) and known biomarkers such as fetal hemoglobin, blood viscosity as well as exploratory oxygen gradient ektacytometry-derived biomarkers in an adult cohort of 50 individuals with SCD (HbSS or HbS/βo-thalassemia) and a pediatric cohort consisting of 177 children with SCD (HbSS or HbS/βo-thalassemia). A substantial number of subjects were on hydroxyurea therapy (64% of adults and 89% of children). Subjects that received a blood transfusion less than three months prior to measurements were excluded from the study. A logistic regression analysis was performed; odds ratios were adjusted for age and hydroxyurea therapy. Results: In the adult cohort, for every 10 mmHg increase in Point of Sickling (PoS, the pO2 tension where RBCs start to sickle, reflecting sickling tendency) the likelihood of >1 acute complication increased; the adjusted odds ratio (aOR) was 3.00 (p=0.015). For every 0.1 increase in EImax (reflecting RBC deformability at normoxia), the aOR was 0.33 (p=0.035, Table 1). In the pediatric cohort, for every 10 mmHg increase in PoS, the likelihood of >1 acute complication increased; the aOR was 1.65 (p=0.006). For every 0.1 increase in EImin (reflecting RBC deformability at hypoxia), the aOR was 0.50 (p=0.007). Fetal hemoglobin and blood viscosity levels were not associated with likelihood of multiple acute complications. However, fetal hemoglobin was associated with reduced likelihood of VOC in adults (aOR of 0.32 for every 10% increment, p=0.010) but not in children (aOR of 0.68, p=0.231, data not shown). In the adult cohort higher EImax was associated with reduced likelihood of VOC (aOR 0.31, p=0.029). There was a trend found for an association between higher PoS and greater likelihood of VOC (aOR 2.22, p=0.050), and no association for EImin. In the pediatric cohort only EImin was associated with VOC (aOR 0.68, p=0.036). Image:Summary/Conclusion: These findings indicate that oxygen gradient ektacytometry generates novel clinically relevant biomarkers and provide a rationale for further development of these biomarkers in the evaluation of novel therapies, as part of clinical care, or clinical trial endpoints. In particular, in assessment of treatment strategies that do not target HbF induction, such as pyruvate kinase activators, voxelotor and l-glutamin, oxygen gradient ektacytometry can generate relevant biomarkers.